Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including the regulation of appetite and metabolism. The effects of leptin were observed by studying mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950. These mice were massively obese and hyperphagic. Leptin itself was discovered in 1994 by Jeffrey M. Friedman and team at the Rockefeller University through the study of those mutant mice. The Ob(Lep) gene (Ob for obese and Lep for leptin) is located on chromosome 7 in humans. Leptin is produced by adipose tissue and interacts with six types of receptor (LepRa–LepRf). LepRb is the only receptor isoform that contains active intracellular signaling domains. This receptor is present in a number of hypothalamic nuclei, where it exerts its effects. Importantly, leptin binds to the Ventral Medial nucleus of the hypothalamus, known as the "satiety center." Binding of leptin to this nucleus signals to the brain that the body has had enough to eat -- a sensation of satiety. A very small group of humans, mostly arising from inbred populations, are also mutant for the leptin gene. These people eat nearly constantly, and may be more than 100 pounds (45 kg) overweight by the age of 7. Thus, circulating leptin levels give the brain a reading of energy storage for the purposes of regulating appetite and metabolism. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and by increasing the activity of neurons expressing α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the receptor at which α-MSH acts in the brain are linked to obesity in humans. Leptin is also regulated (downward) by melatonin during the night. PMID 15311999 Leptin as adiposity signal To date, only leptin and insulin fulfill the criteria of an adiposity signal: * It circulates at levels proportional to body fat. * It enters the central nervous system (CNS) in proportion to its plasma concentration. * Its receptors are found in brain neurons involved in regulating energy intake and expenditure. Mechanism of action It is unknown whether leptin must cross the blood-brain barrier to access receptor neurons, because the blood-brain barrier is somewhat absent in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are. If it does cross the blood-brain barrier, it is unknown whether this occurs via an active or passive process. It is generally thought that leptin might enter the brain at the choroid plexus, where there is intense expression of a form of leptin receptor molecule that might act as a transport mechanism. Once leptin has bound to the Ob-Rb receptor, it activates the molecule stat3, which is phosphorylated and travels to the nucleus, it is presumed, to effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible—among their many other functions—for increasing appetite. There are other intracellular pathways activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them. Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin. These people are said to be resistant to the effects of leptin, in much the same way that people with type 2 diabetes are resistant to the effects of insulin. Thus, obesity develops when people take in more energy than they use over a prolonged period of time, and this excess food intake is not driven by hunger signals, occurring in spite of the anti-appetite signals from circulating leptin. The high sustained concentrations of leptin from the enlarged fat stores result in the cells that respond to leptin becoming desensitized. In mice, leptin is also required for male and female fertility. In mammals generally, and in humans in particular, puberty in females is linked to a critical level of body fat. When fat levels fall below this threshold (as in anorexia), the ovarian cycle stops and females stop menstruating. Leptin is also strongly linked with angiogenesis, increasing VEGF levels. Leptin and reproduction Leptin is produced by the placentaZhao J, townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP. leptin receptor expression increases in placenta, but not in hypothalamus, during gestation in Mus musculus and Myotis lucifungus. Placenta (2004) 25:712-22. Leptin levels rise during pregnancy and fall at parturition. Leptin is also expressed in fetal mebranes and uterine tissue. Uterine muscle contractions are inhibited by leptin.Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ. Inhibitory effect of leptin on human uterine contractility in vitro. Amer J Obstet Gynecol (2006) 195:504-9. Recent Discoveries Professor Cappuccio of the University of Warwick has recently discovered that short sleep duration may lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces Ghrelin which, among other effects, stimulates appetite and creates less leptin which, amongst its many other effects, increases appetite. Next to a biomarker for body fat, serum leptin levels also reflect individual energy balance. Several studies have shown that fasting or following a VLCD diet lowers leptin levels (Dubuc Metabolism 1998; Pratley Am J Physiol 1996; Weigle, J Clin Endocrinol 1997). It might be that on short term leptin is an indicator of energy balance. In line with evolution this system is more sensitive to starvation than to overfeeding (J Clin Endocr Metab, Chinchance 2000), i.e. leptin levels do not rise extensively after overfeeding. It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually in food intake. Although this is a new hypothesis already some data supports this hypothesis (Keim, AM J Clin Nutr 1998; Mars Int J Obesity, 2006). References External links *A discussion of leptin in a bulletin by the Howard Hughes Medical Institute (HHMI) *Leptin and the regulation of body weight in mammals *Leptin: Your brain, appetite and obesity *Leptin Hormone *A good overview of leptin biology from the Science Creative Quarterly Category:Appetite hormone Category:Peptide hormones